Identification and kinetics of a beta-glucuronide metabolite of SN-38 in human plasma after administration of the camptothecin derivative irinotecan.

Irinotecan (7-ethyl-10-[4-[1-piperidino]-1-piperidino]carbonyloxycampothecin) , also known as CPT-11, is a promising semi-synthetic derivative of camptothecin with significant activity against a range of tumor types. The pharmacokinetic behaviour of its principal and presumedly active metabolite, SN-38 (7-ethyl-10-hydroxy-camptothecin), displays wide inter-patient variation. During the high-performance liquid chromatographic (HPLC) analysis of plasma samples collected from a patient given CPT-11, we observed several unidentified peaks that were not present in pre-infusion samples. In this paper we describe the manner in which one of these was determined to be a beta-glucuronide of SN-38. The total plasma concentrations of this metabolite were quantified following digestion with beta-glucuronidase and were found to be greater than those of SN-38 in the patient studied. The elimination phases of the plasma concentration profile of SN-38 and its glucuronide were parallel, suggesting that the transformation of SN-38 to the glucuronide is the rate-limiting step in the elimination of SN-38 and could play a key role in its pharmacokinetics.